Prof. Dr. Mark Greenlee
University of Regensburg

Prof. Dr. John S. Werner
University of California, Davis
Department of Ophthalmology and Vision Science

Macular degeneration is the major cause of legal blindness in industrialized countries, mostly affecting older persons (age related macular degeneration, AMD). It is now possible to understand this disease, not just as a retinal disorder, but in the larger context of neural degenerations. Details of the disease can be imaged in the retina with micrometer precision, while the fibers to central areas can be traced in the living brain using diffusion tensor imaging (DTI). We are identifying groups of individuals with AMD, a group with long-standing macular degeneration that affects young people (Stargardt’s disease) and age-matched normal controls. We will correlate areas of visual loss measured by microperimetry with their changes in the outer retina (photoreceptors and retinal pigmented epithelium) and then trace the projections into the brain using DTI. The results will inform us about changes in the brain associated with early and late-stage macular degeneration. As new and promising treatments to decrease the rate of retinal loss in these patients become available, along with novel treatments involving stem cells and genetic therapies, it will be essential to know what to expect at higher levels in the brain in order to facilitate rehabilitation. A better understanding of age-related macular degeneration is expected as it is now largely considered a retinal disease, but changes in the visual pathways are nearly certain at least in individuals with long-standing retinal lesions. This research is expected to broaden our understanding of neural pathology underlying macular degeneration.

Final report:

Macular degeneration (MD) affects the central retina and gradually destroys high spatial and chromatic central vision. That implies that in patients with MD large portions of the central visual pathways normally receiving afferent signals from the fovea will be unstimulated. The neuro-anatomical consequences of insufficient afferent and efferent stimulation has been reported in many conditions. In the current study, it was assumed that MD, that causes degeneration of the outer retina and photoreceptor dysfunction, could affect inner retinal neurons as well as could provoke microstructural changes in the nerve fibers of central visual pathways.

To test our hypotheses six MD patients and six healthy control subjects were examined in our study. We used spectral-domain optical coherency tomography (SD-OCT) to quantify changes in peripapillary retinal nerve fiber layer (RNFL). Siemens 3T head-only MRI scanner was used to acquire DTI and high-resolution T1-weighted structural. MRI data were processed using Vistalab software (https://github.com/vistalab/vistasoft/). Probabilistic fiber tracking was performed with ConTrack toolbox to identify optic tract (OT) and optic radiations (OR). Fractional anisotropy (FA), axial and radial diffusivity values (AD, RD) were calculated along the OT and OR pathways.

Comparing RNFL thickness in normal eyes to that with MD, we found significant thinning of RNFL thickness at the temporal segment of retina (two-tailed unpaired t-test, p= 0.006, reduced by 16%). RNFL thickness was also reduced in the nasal segment by 7%, although no significant difference between groups was found (two-tailed unpaired t-test, p>0.05). Comparison of average RNFL thickness reveals a significant loss in MD patients (two-tailed unpaired t-test, p<0.0001).

Tract profiles of OT and OR were compared between patients and healthy controls. We found a significant decrease in FA values in MD patients both in OT (Wilcoxon's rank-sum test, p<0.01) and OR (Wilcoxon's rank-sum test, p<0.00001) compared to the age-matched control group.

Further statistical analyses revealed a significant main effect of groups with respect to mean AD in optic radiations (p<0.00001). We observed some changes of AD values in patients’ optic tract as well, although, the changes in optic tract were not significant (p = 0.4). Means of RD value were significantly higher in the optic radiations compared to the control group (Wilcoxon's rank-sum test, p<0.00001). RD showed a trend to increase in patients’ optic tract as well. However, these changes never reached statistical significance (Wilcoxon's rank-sum test, p = 0.08).

Our results indicate that the RNFL and the white matter of the visual pathways are significantly altered in MD patients. Damage to the photoreceptors in MD leads to atrophy of the ganglion cell axons and to corresponding changes in structural properties of central visual pathways.